Neuropeptide antagonists

ABSTRACT

The compoundis a neuropeptide Y antagonist and is effective in treating feeding disorders, cardiovascular diseases and other physiological disorders.

This application is filed claiming priority from co-pending ProvisionalApplication No. 60/117,395 filed Jan. 27, 1999.

BACKGROUND OF INVENTION

1. Field of the Invention

This invention relates to the use of diphenylacetanilides whichselectively bind to mammalian Neuropeptide receptors. It further relatesto the use of these compounds and compositions containing thesecompounds in treating conditions related to an excess of neuropeptide Ysuch as feeding disorders and certain cardiovascular diseases.

2. Description of the Related Art

Neuropeptide Y, a peptide first isolated in 1982, is widely distributedin the central and peripheral neurons and is responsible for a multitudeof biological effects in the brain and the periphery. Various animalstudies have shown that activation of neuropeptide Y1 receptors isrelated to vasoconstriction, Wahlestedt et al Regul. Peptides, 13:307-318 (1986), McCauley and Westfall, J. Pharmacol. Exp. Ther.261:863-868 (1992), and Grundemar et al Br. J. Pharmacol. 105:45-50(1992); and to stimulation of consummatory behavior, Flood and Morley,Peptides, 10:963-966 (1989), Leibowitz and Alexander, Peptides,12:1251-1260 (1991), and Stanley et al Peptides,.13:581-587 (1992).

Grundemar and Hakanson TIPS, May 1994 [Vol. 15], 153-159, state that, inanimals, neuropeptide Y is a powerful stimulus of food intake, and aninducer of vasoconstriction leading to hypertension. They further pointout that low levels of neuropeptide Y (NPY) are associated with loss ofappetite. These reports clearly indicate that compounds that inhibit theactivity of this protein will reduce hypertension and appetite inanimals.

EP0759441 and U.S. Pat. No. 5,576,337 report that physiologicaldisorders caused by neuropeptide Y include:

disorders or diseases pertaining to the heart, blood vessels or therenal system, such as vasospasm, heart failure, shock, cardiachypertrophy, increased blood pressure, angina, myocardial infarction,sudden cardiac death, arrhythmia, peripheral vascular disease, andabnormal renal conditions such as impaired flow of fluid, abnormal masstransport, or renal failure; conditions related to increased sympatheticnerve activity for example, during or after coronary artery surgery, andoperations and sugery in the gastrointestinal tract;

cerebral diseases and diseases related to the central nervous system,such as cerebral infarction, neurodegeneration, epilepsy, stroke, andconditions related to stroke, cerebral vasospasm and hemmorrhage,depression, anxiety, schizophrenia, and dementia;

conditions related to pain or nociception;

diseases related to abnormal gastrointenstinal motility and secretion,such as different forms of ileus, urinary incontinence, and Crohn'sdisease;

abnormal drink and food intake disorders, such as anorexia and metabolicdisorders;

diseases related to sexual dysfunction and reproductive disorders;

conditions or disorders associated with inflammation;

respiratory diseases, such as asthma and conditions related to asthmaand bronchoconstriction; and diseases related to abnormal hormonerelease, such as leutinizing hormone, growth hormone, insulin, andprolactin.

WO 96/14307 refers to substituted benzylamine derivatives whichselectively bind to human neuropeptide Y1 receptors.

SUMMARY OF THE INVENTION

This invention comprises a method of inhibiting or alleviating apathological condition or physiological disorder in a mammalcharacterized by or associated with neuropeptide Y which comprisesadministering to a mammal in need of such treatment a neuropeptide Yinhibiting amount of the compound of the formula:

wherein R is —N(C₂H₅)₂

or a pharmaceutically acceptable salt thereof

In another aspect, this invention comprises a method of inhibiting oralleviating a pathological condition or physiological disorder in amammal characterized by or associated with an excess of neuropeptide Ywhich accompanies administering to a mammal in need of such treatment aneuropeptide Y inhibiting amount of the compound of Formula I shownabove.

This invention also comprises a method of treating a pathologicalcondition wherein said pathological condition or physiological disorderis a feeding disorder such as obesity or bulimia.

In another aspect, this invention comprises a method of inhibiting oralleviating a pathological condition or physiological disorder in amammal wherein said pathological condition or physiological disorder isselected from the group consisting of:

disorders or diseases pertaining to the heart, blood vessels or therenal system, such as vasospasm, heart failure, shock, cardiachypertrophy, increased blood pressure, angina, myocardial infarction,sudden cardiac death, arrhythmia, peripheral vascular disease, andabnormal renal conditions such as impaired flow of fluid, abnormal masstransport, or renal failure;

conditions related to increased sympathetic nerve activity for example,during or after coronary artery surgery, and operations and surgery inthe gastrointestinal tract;

cerebral diseases and diseases related to the central nervous system,such as cerebral infarction, neurodegeneration, epilepsy, stroke, andconditions related to stroke, cerebral vasospasm and hemorrhage,depression, anxiety, schizophrenia, and dementia;

conditions related to pain or nociception;

diseases related to abnormal gastrointenstinal motility and secretion,such as different forms of ileus, urinary incontinence, and Crohn'sdisease;

abnormal drink and food intake disorders, such as anorexia and metabolicdisorders;

diseases related to sexual dysfunction and reproductive disorders;

conditions or disorders associated with inflammation;

respiratory diseases, such as asthma and conditions related to asthmaand bronchoconstriction; and diseases related to abnormal hormonerelease, such as leutinizing hormone, growth hormone, insulin, andprolactin.

The compound of formula I when R is —N(C₂H₅)₂ is basic in nature andcapable of forming a wide variety of salts with various inorganic andorganic acids. The acids that may be used to prepare pharmaceuticallyacceptable acid addition salts of the compound of formula I are thosethat form non-toxic acid addition salts, i.e., salts containingpharmacologically acceptable anions, such as the hydrochloride,hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acidphosphate, isonicotinate, acetate, lactate, salicylate, citrate, acidcitrate, tartrate, pantothenate, bitartrate, ascorbate, succinate,maleate, fumarate, gluconate, glucaronate, saccharate, formate,benzoate, glutamate, methanesulfonate, ethanesulfonate,benzenesulfonate, and p-toluenesulfonate.

DETAILED DESCRIPTION OF THE INVENTION

The compounds of formula I are known in the chemical literature and maybe prepared by the procedures described Muramatsee, et al. TetrahedronLetters No. 23, pp. 2133-2136 (1973); Stevens and French, J. Am. Chem.Soc. 1953, 75, 657-60; and Hoerhold and Eibish, Tetrahedron 1969, 25,4277-4286. These references are hereby incorporated by reference.

Briefly, the compound of formula I wherein R is —N(C₂H₅)₂ is prepared byirradiation of molar equivalents of diphenyidiazomethane andp-diethylamino-phenyl isonitrile. The compound of formula I is acolorless solid, mp 145-6° C.

The acid addition salts of this compound are readily prepared bytreating the base compound with a substantially equivalent amount of thechosen mineral or organic acid in an aqueous solvent or suitable organicsolvent such as methanol or ethanol. Upon evaporation of the solvent,the derived salt is obtained.

The pharmaceutical utility of the compound of Formula I is indicated bythe following assays for human NPY1 and NPY5 receptor activity.

NPY1 Assay

The procedure used is similar to that described by Gordon et al. (J.Neurochem. 55:506-513, 1990). SK-N-MC cells were purchased from ATCC(Rockville, Md.). Cells were maintained at 37° C. and 5% CO₂ inDulbecco's modified essential media (DMEM) with L-glutamine and 110 mg/Lsodium pyruvate, which was supplemented with 10% fetal bovine serum and25 mM HEPES (pH 7.3). The binding assay was performed in 24-well plates(Falcon) when the cells were confluent. Taking care to not disturb thecells on the bottom of the wells, the media was aspirated, and 0.5 ml ofDulbecco's phosphate buffered saline (DPBS) with calcium and magnesiumwere added to each well. The DPBS was aspirated and an additionalaliquot of DPBS was added and aspirated. To begin the assay, bindingbuffer consisting of serum-free DMEM containing 0.5% bovine serumalbumin, 0.1% bacitracin and 0.1 mM phenylmethylsulfonylfluoride wasadded to each well. The cells and the binding buffer preincubated for 30minutes at room temperature, at which point the drug dilution and[¹²⁵I)]PYY (NEN-DuPont: 50000-75000 cpm ˜50 pM) were added to yield afinal volume of 250 ul. Nonspecific binding was defined with 1 mM NPY(porcine or human, Bachem Calif.). After a 3 hour incubation at roomtemperature, the plates were then put on ice and the wells wereaspirated. The cells were washed 4-6 times with 0.5 ml of ice-cold DPBS.A dilute solution of Triton X-100 (1%) was then added to each well.After approximately 1 hour at room temperature, an aliquot from eachwell was transferred to a 12×75 mm test tube, and the amount of [¹²⁵I]was quantitated on a gamma counter with an efficiency of 80-85% (Genesys5000, Laboratory Technologies). IC₅₀ values were calculated with thenon-linear curve fitting program RS/1 (BBN Software Products Corp.,Cambridge, Mass.).

Assay for NPY-5 Binding

[¹²⁵I]PYY Binding at Human NPY Receptors Expressed in Sf9 Cells

Baculovirus-infected Sf9 cells expressing recombinant human NPY 5receptors are harvested at 48 hours. At the time of harvest, cellpellets are resuspended in lysis buffer (20 mM Tris-HCl, pH 7.4, 5 mMEDTA, 0.5 μg/ml leupeptin, 2 μg/ml Aprotonin and 200 mM PMSF) andhomogenized using a Polytron (setting 3, 25-30 seconds). Homogenates arecentrifuged at 4° C. for 5 minutes at 200 x g (˜1.5 rpm) to pellet thenuclei. The supernatant is collected into a fresh tube and centrifugedat 48,000 x g for 10 minutes. Pellets are washed once in lysis bufferand centrifuged. The final pellet is resuspended in PBS and stored inaliquots at −80° C. Purified membranes are washed using PBS andresuspended in binding buffer (50 mM Tris(HCl), pH 7.4, 5 mM KCl, 120 mMNaCl, 2 mM CaCl₂, 1 mM MgCl₂, 0.1% bovine serum albumin (BSA)).Membranes (20 μg/reaction tube) are added to polypropylene tubescontaining 0.035 nM [¹²⁵I]PYY(porcine), displacers ranging from 10⁻¹² Mto 10⁻⁵ M, and buffer to yield a final volume of 0.5 mL. Nonspecificbinding is determined in the presence of 1 μM NPY(human) and accountsfor 10% of total binding. Following a 2 hour incubation at roomtemperature, the reaction is terminated by rapid vacuum filtration.Samples are filtered over presoaked GF/C Whatman filters (1.0%polyethylenemine) and rinsed 2 times with 5 mL cold binding bufferwithout BSA. A gamma counter is used to count filters with an efficiencyof 85%. IC₅₀ values were calculated with the non-linear curve fittingprogram RS/1 (SigmaPlot, Jandel).

Compounds of Formula I showed the following binding constants in theNPY5

R Ki nM —N(C₂H₅)₂ 8 —CH₃ 800

14

Functional Assay for NPY Receptors Expressed in Oocytes

Experiments were performed on Xenopus oocytes. Oocytes were prepared andmaintained using standard protocols (Dascal and Lotan, in Methods inMolecular Biology; Protocols in Molecular Neurobiology, eds. Longstaff &Revest, Humana, Clifton, N.J., 13:1992). For the present experiments,oocytes were obtained from 6 frogs. Oocytes were recorded from 2-7 daysfollowing coinjection of GIRK1 and the H17 NPY-1 or NPY-5 subtype mRNA(25 ng of each, 50 nL total volume).

Two electrode voltage clamp recordings were carried out using a WarnerInstruments Oocyte clamp OC 725B. Data were collected on a Macintoshmicrocomputer and analyzed using Superscope software. Voltage andcurrent electrodes were pulled from glass tubing (1.5 mM O.D.) on aBrown/Flaming micropipet puller (Sutter Instruments, model P-87).Electrodes contained 3M KCl and had resistances of 0.5-2 MOhms. Oocyteswere bathed in normal external solution containing; 90 mM NaCl, 1 mMKCl, 1 mM MgCl₂, 1 mM CaCl₂, 5 mM HEPES, pH=7.4. Before NPY agonists orantagonists were introduced, a high K⁺ solution containing; 1 mM NaCl,90 mM KCl, 1 mM MgCl₂, 1 mM CaCl₂, 5 mM HEPES was applied to permitrecording of the inwardly rectifying K⁺ current. Drugs were applieddiluted in the high K⁺ media.

100 μM stocks of NPY, PP or NPY peptide fragments or PYY peptidefragments were prepared in water and frozen until needed.

Oocytes were voltage-clamped at −80 mV with two electrodes. Oocytes wereinitially superfused with normal external medium (approximate flow rate4 ml/min.). Before drugs were applied, cells were superfused with highK⁺ solution to permit activation of the inwardly rectifying K⁺ current.In oocytes coinjected with NPY receptor and GIRK1 mRNA, the NPY agonistinduced an additional inward current over the resting K⁺ current causedby high K⁺ medium. Because responses desensitized at slow, but varyingrates, cumulative dose applications were administered to generateconcentration response curves. Two to four doses of agonist were appliedto each cell. Agonist dose responses in each cell were normalizedagainst the response to a maximal concentration of human NPY. Doseresponse curves were fit with a logistic equation using Kaleidagraphsoftware (Abelbeck software, Reading, Pa.).

The compound of formula I or a pharmaceutically acceptable salt thereof(the active compound) may be administered orally, topically,parenterally, by inhalation or spray or rectally in dosage unitformulations containing conventional non-toxic pharmaceuticallyacceptable carriers, adjuvants and vehicles. The term parenteral as usedherein includes subcutaneous injections, intravenous, intramuscular,intrasternal injection or infusion techniques. In addition, there isprovided a pharmaceutical formulation comprising a compound of generalformula I and a pharmaceutically acceptable carrier. The active compoundmay be present in association with one or more non-toxicpharmaceutically acceptable carriers and/or diluents and/or adjuvantsand if desired other active ingredients. The pharmaceutical compositionscontaining the active compound may be in a form suitable for oral use,for example, as tablets, troches, lozenges, aqueous or oily suspensions,dispersible powders or granules, emulsion, hard or soft capsules, orsyrups or elixirs.

Compositions intended for oral use may be prepared according to anymethod known to the art for the manufacture of pharmaceuticalcompositions and such compositions may contain one or more agentsselected from the group consisting of sweetening agents, flavoringagents, coloring agents and preserving agents in order to providepharmaceutically elegant and palatable preparations. Tablets contain theactive compound in admixture with non-toxic pharmaceutically acceptableexcipients which are suitable for the manufacture of tablets. Theseexcipients may be for example, inert diluents, such as calciumcarbonate, sodium carbonate, lactose, calcium phosphate or sodiumphosphate; granulating and disintegrating agents, for example, cornstarch, or alginic acid; binding agents, for example starch, gelatin oracacia, and lubricating agents, for example magnesium stearate, stearicacid or talc. The tablets may be uncoated or they may be coated by knowntechniques to delay disintegration and absorption in thegastrointestinal tract and thereby provide a sustained action over alonger period. For example, a time delay material such as glycerylmonostearate or glyceryl distearate may be employed.

Formulations for oral use may also be presented as hard gelatin capsuleswherein the active ingredient is mixed with an inert solid diluent, forexample, calcium carbonate, calcium phosphate or kaolin, or as softgelatin capsules wherein the active ingredient is mixed with water or anoil medium, for example peanut oil, liquid paraffin or olive oil.

Aqueous suspensions contain the active material in admixture withexcipients suitable for the manufacture of aqueous suspensions. Suchexcipients are suspending agents, for example sodiumcarboxymethylcellulose, methylcellulose, hydropropylmethylcellulose,sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia;dispersing or wetting agents may be a naturally-occurring phosphatide,for example, lecithin, or condensation products of an alkylene oxidewith fatty acids, for example polyoxyethylene stearate, or condensationproducts of ethylene oxide with long chain aliphatic alcohols, forexample heptadecaethyleneoxycetanol, or condensation products ofethylene oxide with partial esters derived from fatty acids and ahexitol such as polyoxyethylene sorbitol monooleate, or condensationproducts of ethylene oxide with partial esters derived from fatty acidsand hexitol anhydrides, for example polyethylene sorbitan monooleate.The aqueous suspensions may also contain one or more preservatives, forexample ethyl, or n-propyl p-hydroxybenzoate, one or more coloringagents, one or more flavoring agents, and one or more sweetening agents,such as sucrose or saccharin.

Oily suspensions may be formulated by suspending the active ingredientin a vegetable oil, for example arachis oil, olive oil, sesame oil orcoconut oil, or in a mineral oil such as liquid paraffin. The oilysuspensions may contain a thickening agent, for example beeswax, hardparaffin or cetyl alcohol. Sweetening agents such as those set forthabove, and flavoring agents may be added to provide palatable oralpreparations. These compositions may be preserved by the addition of ananti-oxidant such as ascorbic acid.

Dispersible powders and granules suitable for preparation of an aqueoussuspension by the addition of water provide the active ingredient inadmixture with a dispersing or wetting agent, suspending agent and oneor more preservatives. Suitable dispersing or wetting agents andsuspending agents are exemplified by those already mentioned above.Additional excipients, for example sweetening, flavoring and coloringagents, may also be present.

Pharmaceutical compositions of the invention may also be in the form ofoil-in-water emulsions. The oily phase may be a vegetable oil, forexample olive oil or arachis oil, or a mineral oil, for example liquidparaffin or mixtures of these. Suitable emulsifying agents may benaturally occurring gums, for example gum acacia or gum tragacanth,naturally-occurring phosphatides, for example soy bean, lecithin, andesters or partial esters derived from fatty acids and hexitol,anhydrides, for example sorbitan monoleate, and condensation products ofthe said partial esters with ethylene oxide, for example sweetening,flavoring and coloring agents, may also be present.

Syrups and elixirs may be formulated with sweetening agents, for exampleglycerol, propylene glycol, sorbitol or sucrose. Such formulations mayalso contain a demulcent, a preservative and flavoring and coloringagents. The pharmaceutical compositions may be in the form of a sterileinjectable aqueous or oleaginous suspension. This suspension may beformulated according to the known art using those suitable dispersing orwetting agents and suspending agents which have been mentioned above.The sterile injectable preparation may also be sterile injectablesolution or suspension in a non-toxic parentally acceptable diluent orsolvent, for example as a solution in 1,3butanediol. Among theacceptable vehicles and solvents that may be employed are water,Ringer's solution and isotonic sodium chloride solution. In addition,sterile, fixed oils are conventionally employed as a solvent orsuspending medium. For this purpose any bland fixed oil may be employedincluding synthetic mono- or diglycerides. In addition, fatty acids suchas oleic acid find use in the preparation of injectables.

The active compound may also be administered in the form ofsuppositories for rectal administration of the drug. These compositionscan be prepared by mixing the drug with a suitable non-irritatingexcipient which is solid at ordinary temperatures but liquid at therectal temperature and will therefore melt in the rectum to release thedrug. Such materials are cocoa butter and polyethylene glycols.

The active compound may be administered parenterally in a sterilemedium, The drug, depending on the vehicle and concentration used caneither be suspended or dissolved in the vehicle. Advantageously,adjuvants such as local anesthetics, preservatives and buffering agentscan be dissolved in the vehicle.

Dosage levels of the order of from about 0.1 mg to about 15 mg of activecompound per kilogram of body weight per day are useful in the treatmentof the above-indicated conditions (about 7 mg to about 1 g per humanpatient per day). The amount of active compound that may be combinedwith the carrier materials to produce a single dosage form will varydepending upon the host treated and the particular mode ofadministration. Dosage unit forms will generally contain between fromabout 1 mg to about 500 mg of an active compound.

It will be understood, however, that the specific dose level for anyparticular patient will depend upon a variety of factors including theactivity of the specific compound employed, the age, body weight,general health, sex, diet, time of administration, route ofadministration and rate of excretion, drug combination and the severityof the particular disease undergoing therapy.

As a consequence of its action in treating pathological conditions thecompound of the present invention possess utility for treatment ofungulate animals such as swine, cattle, sheep, and goats. The activecompound of the invention can additionally be used for the treatment ofhousehold pets, for example companion animals such as dogs and cats. Theadministration of the active compound of formula I can be effectedorally or parenterally. An amount of the active compound of formula I isadministered such that an effective dose is received, generally a dailydose which, when administered orally to an animal is usually between0.01 and 20 mg/kg of body weight, preferably between 0.05 and 10 mg/kgof body weight. Conveniently, the medication can be carried in drinkingwater so that a therapeutic dosage of the agent is ingested with thedaily water supply. The agent can be directly metered into drinkingwater, preferably in the form of a liquid, water-soluble concentrate(such as an aqueous solution of a water soluble salt).

Conveniently, the active compound can also be added directly to thefeed, as such, or in the form of an animal feed supplement, alsoreferred to as a premix or concentrate. A premix or concentrate oftherapeutic agent in a carrier is more commonly employed for theinclusion of the agent in the feed. Suitable carriers are liquid orsolid, as desired, such as water, various meals such as alfalfa meal,soybean meal, cottonseed oil meal, linseed oil meal, corncob meal andcorn meal, molasses, urea, bone meal, and mineral mixes such as arecommonly employed in poultry feeds. A particularly effective carrier isthe respective animal feed itself; that is, a small portion of suchfeed. The carrier facilitates uniform distribution of the activematerials in the finished feed with which the premix is blended. It isimportant that the compound be thoroughly blended into the premix and,subsequently, the feed. In this respect, the agent may be dispersed ordissolved in a suitable oily vehicle such as soybean oil, corn oil,cottonseed oil, and the like, or in a volatile organic solvent and thenblended with the carrier. It will be appreciated that the proportions ofactive material in the concentrate are capable of wide variation sincethe amount of agent in the finished feed may be adjusted by blending theappropriate proportion of premix with the feed to obtain a desired levelof therapeutic agent.

High potency concentrates may be blended by the feed manufacturer withproteinaceous carrier such as soybean oil meal and other meals, asdescribed above, to produce concentrated supplements which are suitablefor direct feeding to animals. In such instances, the animals arepermitted to consume the usual diet. Alternatively, such concentratedsupplements may be added directly to the feed to produce a nutritionallybalanced, finished feed containing a therapeutically effective level ofa compound according to the invention. The mixtures are thoroughlyblended by standard procedures, such as in a twin shell blender, toensure homogeneity.

If the supplement is used as a top dressing for the feed, it likewisehelps to ensure uniformity of distribution of the active material acrossthe top of the dressed feed.

Drinking water and feed effective for treating domestic animals aregenerally prepared by mixing the compound of the invention with asufficient amount of animal feed to provide from about 10⁻³ to 500 ppmof the compound in the feed or water.

The preferred medicated swine, cattle, sheep and goat feeds generallycontain from 1 to 400 grams of active compound per ton of feed, theoptimum amount for these animals usually being about 50 to 300 grams perton of feed.

The preferred poultry and domestic pet feeds usually contain about 1 to400 grams and preferably 10 to 400 grams of active compound per ton offeed.

For parenteral administration in animals, the compounds of the presentinvention may be prepared in the form of a paste or a pellet andadministered as an implant, usually under the skin of the head or ear ofthe animal in which increase in lean meat deposition and improvement inlean meat to fat ratio is sought.

In general, parenteral administration involves injection of a sufficientamount of the compound of the present invention to provide the animalwith 0.01 to 20 mg/kg/day of body weight of the active ingredient. Thepreferred dosage for poultry, swine, cattle, sheep, goats and domesticpets is in the range of from 0.05 to 10 mg/kg/day of body weight ofactive ingredient.

What is claimed is:
 1. A method of inhibiting or alleviating apathological condition or physiological disorder in a mammalcharacterized by or associated with neuropeptide Y which comprisesadministering to a mammal in need of such treatment a neuropeptide Yinhibiting amount of the compound of the formula:

wherein R is selected from —N(C₂H₅)₂, —CH₃ and

or a pharmaceutically acceptable salt thereof.
 2. A method of claim 1wherein said pathological condition or physiological disorder is afeeding disorder such as obesity or bulimia.
 3. A method of claim 1wherein said pathological condition or physiological disorder isselected from the group consisting of: disorders or diseases pertainingto the heart, blood vessels or the renal system, such as vasospasm,heart failure, shock, cardiac hypertrophy, increased blood pressure,angina, myocardial infarction, sudden cardiac death, arrhythmia,peripheral vascular disease, and abnormal renal conditions such asimpaired flow of fluid, abnormal mass transport, or renal failure;conditions related to increased sympathetic nerve activity for example,during or after coronary artery surgery, and operations and surgery inthe gastrointestinal tract; cerebral diseases and diseases related tothe central nervous system, such as cerebral infarction,neurodegeneration, epilepsy, stroke, and conditions related to stroke,cerebral vasospasm and hemorrhage, depression, anxiety, schizophrenia,and dementia; conditions related to pain or nociception; diseasesrelated to abnormal gastrointenstinal motility and secretion, such asdifferent forms of ileus, urinary incontinence, and Crohn's disease;abnormal drink and food intake disorders, such as anorexia and metabolicdisorders; diseases related to sexual dysfunction and reproductivedisorders; conditions or disorders associated with inflammation;respiratory diseases, such as asthma and conditions related to asthmaand bronchoconstriction; and diseases related to abnormal hormonerelease, such as leutinizing hormone, growth hormone, insulin, andprolactin.
 4. A pharmaceutical composition for inhibiting or alleviatinga pathological condition or physiological disorder in a mammalcharacterized by or associated with an excess of neuropeptide Y, whichcomprises the compound of the formula:

wherein R is selected from —N(C₂H₅)₂, —CH₃ and

or a pharmaceutically acceptable salt thereof.